Thio-Claisen rearrangement used in preparing anti-β-functionalized γ,δ-unsaturated amino acids: Scope and limitations

Article abstract of DOI:10.1021/jo201753q

Multifunctionalized amino acids, especially amino acids with unsaturation, are important, demanding building blocks in peptide chemistry. Here we present a summary of our most recent study using the thio-Claisen rearrangement for the synthesis of anti-β-f

Full text of DOI:10.1021/jo201753q

Article
pubs.acs.org/joc
Thio-Claisen Rearrangement Used in Preparing Anti-β-Functionalized
γ,δ-Unsaturated Amino Acids: Scope and Limitations
Zhihua Liu,† Sukeshi J. Mehta,† Kwang-Soo Lee,† Bryan Grossman,† Hongchang Qu,† Xuyuan Gu,‡
Gary S. Nichol,† and Victor J. Hruby*,†
†Department of Chemistry and Biochemistry, University of Arizona, 1306 East University Boulevard, Tucson, Arizona 85721, United
States
‡Small Molecule Pharmaceuticals, Nektar Therapeutics, 490 Discovery Drive, Huntsville, Alabama 35758, United States
S
* Supporting Information
ABSTRACT: Multifunctionalized amino acids, especially
amino acids with unsaturation, are important, demanding
building blocks in peptide chemistry. Here we present a
summary of our most recent study using the thio-Claisen
rearrangement for the synthesis of anti-β-functionalized γ,δ-
unsaturated amino acids. Investigations on scope, limitations,
chemoselectivities and stereoselectivities regarding an FeBr3-catalyzed allylation strategy and a thio-enolate dianion formation
strategy for asymmetric thio-Claisen rearrangement are documented. An explanation of the chirality crossover observed between
the Eschenmoser−Claisen rearrangement and the thio-Claisen rearrangement is proposed. Novel optically active Nα-protected
amino acids with biologically interesting functional groups were prepared for the first time.
to be efficient in preparing syn-β-substituted γ,δ-unsaturated
amino acids.22−27 This method was further extended by Ohfune
and co-workers.28,29 Inspired by the seminal work from
Welch30,31 and Rawal32 on the Claisen rearrangement, our
group developed a highly asymmetric Eschenmoser−Claisen
rearrangement33,34 (ECR) and the thio-Claisen rearrange-
ment35,36 (TCR) methods for the synthesis of anti-β-
functionalized, γ,δ-unsaturated amino acids. With the aim of
examining the scope and limitations of these methodologies
and their application in producing novel amino acids, we
initiated an in-depth study with a focus on TCR methodology.
This study includes both the FeBr3-catalyzed allylation strategy
and the thio-enolate dianion strategy.
INTRODUCTION
■
Peptides are among the most important modulators and
information carriers throughout the human body. Their merits,
such as high potency, high specificity, and low toxicity, make
them appealing molecules for pharmaceutical applications.
According to data in 2007, there are 67 peptides and
peptidomimetics already marketed in the world targeting 29
disease indications, and these numbers are expected to have
continuous growth in the next decade.1 With this trend
continuing, there is a concomitant demand to explore how to
efficiently modify peptides and improve their bioavailability,
stability, potency, receptor subtype selectivity, etc.2 Because of
the convenience of preparing peptides via solid phase
chemistry,3 it is inarguable that incorporating nonproteinogenic
Nα-protected amino acids with required chemical, physical, and
pharmacological properties during the synthesis is a straightfor-
ward solution.4−8
β-Functionalized γ,δ-unsaturated amino acids have drawn
significant research interest, initially due to their natural
occurrence and irreversible enzyme inhibitory activities.9−12
More recently, their unique chemical and structural properties
make them valuable tools in general peptide research. They
carry β-position functionalization that could offer desired
pharmacophores. The γ,δ-double bond, which is orthogonal to
standard solid-phase peptide synthesis conditions, provides a
wide selection of chemistries for on-resin and postcleavage
modifications,13−15 for example, site-specific peptide cycliza-
tion,16,17 glycosylation,18 and isotope labeling.19 The Claisen
rearrangement is one of the most efficient strategies to prepare
these amino acids due to its high asymmetric selectivity.20,21
Kazmaier and co-workers have developed a chelation ester−
enolate Claisen rearrangement method which has been proven
RESULTS AND DISCUSSION
■
Having successfully developed an FeBr3-catalyzed allylation
strategy for TCR methodology,36 we were eager to examine the
effectiveness of the reaction sequence in the preparation of
optically active amino acids. Theoretically, it should transfer
chirality with a high efficiency as we reported before. To avoid
possible low asymmetric induction caused by rotomers, we
chose a C2-symmetric chiral auxiliary instead of nonsymmetric
ones.31 Three commercially available or easily accessible C2-
symmetric chiral pyrrolidine derivatives 1−3 were used.37,38
They were first coupled to N-Cbz-protected glycine and then
converted into thioamides 7−9 in almost quantitative yields.39
The thioamides were S-allylated with a FeBr3-catalyzed
alkylation. Once the reaction was complete as monitored by
TLC, the reaction mixture was cooled to −78 °C and the thio-
Received: September 6, 2011
Published: December 27, 2011
© 2011 American Chemical Society
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Scheme 1. Asymmetric TCR Reaction with C2-Symmetric Chiral Auxiliaries
Claisen rearrangement was initiated by deprotonation and
raising the reaction temperature.36 All reactions proceeded
smoothly (Scheme 1) to give the desired products, and the
results are summarized in Table 1. Chiral HPLC was used to
enhancement (entries 10a, 11a, 12a). A non-C2-symmetric
chiral auxiliary coupled thioamide 13 was used as a control
experiment, and a mixture of diastereomers was isolated
showing very little or no diastereoselectivity.
We also studied the compatibility of different protecting
groups for the α-amino group and this methodology. Our
research group is interested in using these amino acids to make
peptide dicarba analogues17 with solid-phase peptide synthesis
techniques. Therefore, we chose the four most commonly used
carbamate protecting groups in solid-phase peptide synthesis:
Fmoc, Boc, Cbz, and Alloc. The Fmoc-protected substrates
gave a complex mixture of products after reaction and could not
be identified, presumably due to the lack of stability of Fmoc
group when exposed to bases at an elevated temperature
overtime. The other carbamate protecting groups showed
unequivocal compatibility with the FeBr3-catalyzed allylation
strategy for TCR. We noticed that the size of protecting group
did not affect the diastereoselectivity, providing additional
support for transition state model A, where the asymmetric
introduction originated from the interaction between the chiral
auxiliary and the allyl group, and not the carbamate protecting
group. We were also delighted to see a moderate increase in the
yield as the size of protecting group decreased. Presumably, this
is caused by less steric repulsion between the allyl fragment and
the Nα protecting group (A in Scheme 1). This effect is
especially obvious when there is a cis substitution in the allyl
bromide starting material (Table 2). Thus, in the case of 3,3-
dimethylallyl bromide and 3-bromocyclohexene, we did not
observe Nα-Boc protected rearrangement products 23b and
23d. However, by choosing a less sterically bulky Cbz group,
we were able to isolate the desired products (Scheme 2). The
least sterically bulky Alloc protecting group resulted in a further
increase in yields. Notably, an amide functional group could be
introduced (24c); anti/syn selectivity was excellent, presumably
for reasons similar to those of ester substituents. However, 24c
was obtained with a lower yield presumably because of the
steric hindrance of the tertiary amide group. In addition, the
bromo enamide did show less reactivity than the bromo enester
in the alkylation step.
Table 1. Results of Enantioselective TCR Reaction for
Synthesis of Anti-β-Functionalized γ,δ-Unsaturated
Thioamides
*
**
Diastereomeric
Anti: 2S,3S and 2R,3R. Syn: 2S,3R and 2R,3S.
excess between two anti isomers: anti major, 2S,3S; anti minor, 2R,3R.
a
b
c
Determined by weight. Determined by chiral HPLC. Isolated yield
of total isomers.
analyze the diastereoselectivities of these reactions. We
observed a trend of moderate diastereoselectivity increase as
the size of R group on the chiral auxiliary was increased from
CH3 to CH2OMe and Ph, suggesting sterically controlled
asymmetric induction. We also noticed that when there is a
conjugated carbonyl group in the allylic bromide, this method
gave superior selectivity with only one diastereomer isolated in
most cases. This observation offers further evidence for our
previously reported bicyclic transition state model A,36 which
gives additional transition state stabilization. When the carbonyl
group is at R1 position, it is not possible to form the bicyclic
transition state structure; there was no diastereoselectivity
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DMPU41 aimed at reducing the enolate−metal chelation,42,43
we hardly observed any improvement. We also tried several
other bases to generate enolate with different counterions, and
those efforts did not solve the problem either. C-Allylation
products were isolated almost exclusively, and this process has
Table 2. Results of Asymmetric TCR Reaction for Synthesis
of Anti-β-Substituted γ,δ-Unsaturated Thioamide
1
poor stereocontrol as indicated by H NMR and chiral HPLC
studies. In any case, we conclude that C-allylation is a serious
side reaction in the TCR reaction with the thio-enolate dianion
strategy when certain substrates are used.
Despite the failure to obtain the expected rearrangement
products from certain thioamide substrates, the TCR reaction
using a thio-enolate dianion strategy is fast and clean: a typical
TCR reaction expoiting this strategy takes about 4 h for
completion, while one using the FeBr3-catalyzed allylation
strategy generally requires 2 days. As a side-by-side comparison
of the two TCR strategies (Scheme 4, Table 3) reveals, the
thio-enolate strategy gave slightly higher yields. When there are
bulky substituents in the allyl bromide starting materials, the
reaction was still valid and gave products with reasonable yields.
The TCR reaction using the FeBr3-catalyzed allylation strategy
is inarguably a general method: the much more mild reaction
conditions make it compatible with multiple functional groups,
protecting groups, and auxiliaries. Both strategies provided
excellent asymmetric introduction with no significant differ-
ences. The structure of compound 28c was determined by an
X-ray crystallography study, and this confirmed the absolute
stereochemistry of the compound (Figure 1).
a
b
1
Determined by H NMR. Isolated yield of total isomers.
Converting the thioamide into the carboxylic acid has been
studied by us previously.35,36 For this work, we chose a three-
step oxidation−iodolactonization−reduction method (Scheme
5) over a one-pot alkylation−reduction−oxidation method
because it resulted in higher yields and was tolerant of those
thioamides carrying alkylation-labile functional groups. After
the thioamides were oxidized, the crude products were used
without further purification to form iodolactones. The
carboxylic acid was obtained from zinc reductive elimination
with lactone ring-opening. The results are summarized in Table
4. Amino acids with assorted auxiliaries and protecting groups
were selected for the study. All four auxiliaries could be
removed smoothly, giving the desired amino acids with good
yields. Little or no epimerization or racemization was detected
during this process. It is worth pointing out that we could not
covert compound 24c into the desired amino acid because of
the similar reactivities of the two tertiary amide functional
groups in the molecule after oxidation.
The TCR exploiting a thio-enolate dianion strategy also was
investigated. According to our recent experiences with C2-
symmetric chiral auxiliary 3, initial LDA or n-Bu-Li treatment of
the thioamide should generate a thio-enolate dianion, which
presumably would be S-allylated with addition of the allylic
bromide and give the TCR product upon increasing the
reaction temperature. To our surprise, the only major products
identified and characterized were the C-allylation products 29−
32 (Scheme 3). When we monitored the reaction progress
involving auxiliaries 1 and 2 with TLC, we did not observe a
transient intermediate spot as with auxiliary 3, which was
supposed to be the S-allylated rearrangement precursor. It is
well established that the regioselectivity of the enolate ambident
anion is affected by the solvent and the counterion.40 At first,
we assumed that the low reactivity of the sulfur anion might be
caused by lithium metal chelation. With addition of HMPA or
Scheme 2. Nα-Protecting Group Compatibility Study with TCR Reaction
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Scheme 3. C-Alkylation vs S-Alkylation in TCR Reaction with Thio-enolate Strategy
Scheme 4. Comparison between TCR Reactions Exploiting Thio-Enolate Strategy and FeBr3-Catalyzed Allylation Strategy
Table 3. Results of Comparing Thio-enolate Strategy and FeBr3-Catalyzed Allylation Strategy Used in Asymmetric TCR
Reaction for Synthesis of Anti-β-Substituted γ,δ-Unsaturated Thioamide
*
**
Anti: 2S,3S and 2R,3R. Syn: 2S,3R and 2R,3S. Diastereomeric excess between two anti isomers: anti major, 2S,3S; anti minor, 2R,3R.
a
b
c
Determined by weight. Determined by chiral HPLC. Isolated yield of total isomers.
We noticed that the absolute configuration of the TCR
products is the opposite of the ECR reaction products when
the same chiral auxiliary was used (Figure 2-I). Both reactions
have similar rearrangement intermediates, and the only
difference between them is the oxygen and sulfur. Interestingly
enough, they give products of opposite chirality with excellent
selectivities, respectively. This could be of great value in organic
synthesis: the more expensive amino acids enantiomer could be
prepared from the cheaper chiral auxiliary enantiomer. To
understand and take advantage of these phenomena, we started
by looking at X-ray crystallography studies data. In the crystal
structure of phenoxathiin,44 the bond length of C−O single
bond is 1.40 Å, and the bond length of C−S single bond is 1.75
Å. The bond angle of C−O−C is measured 20° larger than the
bond angle of C−S−C. The more acute C−S−C bond angle
suggests the participation of d orbitals in the bonding of S,
which has also been observed in multiple crystal structure
determinations.45 Base on these studies, we hypothesized that
the shorter C−O bond length and larger C−O−C bond angle
brought the CH2 group from crotyl alcohol close to the
dimethylpyrrolidinyl auxiliary in ECR transition state, making
model B less favored than model B′ (Figure 2-II, left). In TCR
transition state, model C would be more favored than model C′
in which the more acute C−S−C bond angle and longer bond
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Figure 1. X-ray crystal structure of compound 28c.
Scheme 5. Amino Acid Generation from Thioamides
consistent with C being the transition-state model. The ECR
lost selectivities significantly, which suggests the reaction was
struggling in both disfavored B and B′ transition state models
(Figure 2-III, left). It has to be pointed out here that
compounds 36b and 28f are the closest compounds we can
make for comparison. We have mentioned in our previous
studies that the diphenylpyrrolidinyl auxiliary was not
compatible with the ECR reaction.33
Table 4. Results of Preparing Optically Active Anti-β-
Functionalized γ,δ-unsaturated amino acids
SUMMARY
■
Herein we have elaborated on our studies of the thio-Claisen
rearrangement in the synthesis of anti-β-functionalized γ,δ-
unsaturated amino acids. In the course of this investigation, the
TCR methodologies gave excellent diastereoselectivities and
enantioselectivities with both the thio-enolate dianion strategy
and the FeBr3-catalyzed allylation strategy. Except for Fmoc-
protected amino acids, other commonly used N-protected
amino acids were readily prepared with excellent optical
purities. The TCR reaction using the thio-enolate dianion
strategy is limited by C-alkylation, but it is a fast and clean
reaction that is generally complete in around 4 h and gives
excellent yields even for substrates with significant steric
hindrance. The TCR reaction using the FeBr3-catalyzed
allylation strategy is a mild and general method that allows us
to introduce multiple new functional groups into the products
and does not suffer from C-alkylation side reaction problems.
However, its efficiency can be sensitive to the steric
environment of the reaction. We also gained a preliminary
understanding of the chirality cross over problem between
TCR and ECR reactions. Research on using these novel amino
acids studying peptide dicarba analogues and β-turn structures
are ongoing.
*
**
Anti: 2S,3S and 2R,3R; syn: 2S,3R and 2R,3S. Enantiomeric excess
between two anti isomers: anti major: 2S,3S; anti minor: 2R,3R.
a
b
c
Determined by weight. Determined by chiral HPLC. Isolated yield
of total isomers.
length made the alkene moiety from crotyl bromide clash with
the methyl group from chiral auxiliary (Figure 2-II, right).
To prove this hypothesis, we thought that by comparing the
diastereoselectivities from both reactions when a cis substitution
is presented could provide new insights. This is because when a
cis substitution is presented in the ECR reaction, both B and B′
would have stereic clashes, resulting in lower diastereoselectiv-
ity (Figure 2-III, left). On the contrary, when a cis substituion is
presented for TCR reaction, this makes C still favored since the
proximal methyl group on the auxiliary is pointing away from
the allylic group moiety, creating an empty space that
accommodates cis substitution. C′ is further disfavored because
an increased steric clash is introduced from the cis substitution
with the methyl group from pyrrolidine ring. This should result
in an enhanced diastereoselectivity in the TCR reaction (Figure
2-III, right). The experimental validation of this hypothesis was
presented in Table 5. The TCR reaction gave better
diastereoselectivities (compound 10e and 28f), and only one
diastereopure compound was isolated in each case, which is
EXPERIMENTAL SECTION
■
General Procedure for the Preparation of Compounds 7−9,
13, 18−21, and 27. A 250 mL round-bottom flask was charged with
compound 4, 5, 14−17, and 26 (10.0 mmol) dissolved in toluene (100
mL) with Lawesson’s reagent (4.8 g, 12.0 mmol) and sodium
bicarbonate (8.4 g, 100.0 mmol). The reaction was stirred and refluxed
at 120 °C until starting material was no longer present by TLC
analysis (about 3 h). Then the reaction was cooled to ambient
temperature and diluted with 200 mL of EtOAc. The solution was
filtered and washed with a 5% citric acid solution (50 mL × 2 and
brine (50 mL × 1), and the organic layer was collected and dried over
anhydrous MgSO4. The dry solution was filtered and concentrated
under reduced pressure. The residues collected were purified by flash
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Figure 2. Proposed transition-state models for TCR and ECR reactions.
57.3, 48.6, 31.2, 28.5, 20.8, 16.8; HRMS (ESI) calcd for C16H23N2O2S
(MH+) 307.1475, found 307.1472.
Table 5. Results of Comparing ECR and TCR
Diastereoselectivities
Benzyl (2-((2S,5S)-2,5-Bis(methoxymethyl)pyrrolidin-1-yl)-2-
thioxoethyl)carbamate (8). Amide 5 (541.4 mg, 1.55 mmol),
Lawesson’s reagent (751 mg, 1.86 mmol), and sodium bicarbonate
(1300 mg, 15.5 mmol) were reacted and worked up as described
above. Product 8: colorless oil, 566 mg, yield 99%; Rf = 0.40 (hexanes/
EtOAc = 1:1); [α]24.6D +39.1 (c 1.14, MeOH); IR (NaCl) 2928, 1720,
1447, 1113; 1H NMR (500 MHz, CDCl3) δ 7.58−7.05 (m, 5H), 6.22
(br, 1H), 5.12 (s, 2H), 4.79 (t, J = 6.0 Hz, 1H), 4.34 (dd, J = 16.5, 5.0
Hz, 2H), 4.10 (dd, J = 16.7, 5.0 Hz, 1H), 3.77 (dd, J = 9.5, 2.4 Hz,
1H), 3.66 (dd, J = 9.4, 6.6 Hz, 1H), 3.45 (dd, J = 9.5, 4.5 Hz, 1H),
3.38−3.12 (m, 6H), 2.27 (dd, J = 13.2, 6.3 Hz, 1H), 2.12 (td, J = 12.9,
6.8 Hz, 1H), 2.07−1.86 (m, 2H); 13C NMR (125 MHz, CDCl3) δ
197.5, 155.8, 136.4, 128.3, 127.9, 127.8, 73.4, 69.1, 66.7, 63.2, 61.2,
59.0, 58.8, 49.3, 27.9, 25.4; HRMS (ESI) calcd for C18H27N2O4S
(MH+) 367.1686, found 367.1687.
(S)-Benzyl (2-(2-(methoxymethyl)pyrrolidin-1-yl)-2-thioxoethyl)-
carbamate (13): IR (NaCl) 3322, 2930, 1717, 1456, 1215, 1109;
[α]24.3D −49.4 (c 0.60, MeOH); HRMS (ESI) calcd for C16H23N2O3S
(MH+) 323.1424, found 323.1430.
*
**
Diastereomeric
Anti: 2S,3S and 2R,3R; syn: 2S,3R and 2R,3S.
excess between two anti isomers: anti major: 2S,3S; anti minor: 2R,3R.
(9H-Fluoren-9-yl)methyl (2-(Pyrrolidin-1-yl)-2-thioxoethyl)-
carbamate (18). Amide 14 (887 mg, 2.47 mmol), Lawesson’s reagent
(1200 mg, 2.96 mmol), and sodium bicarbonate (2000 mg, 24.7
mmol) were reacted and worked up as described above. Product 18:
white solid, 813 mg, yield 90%; Rf = 0.55 (hexanes/EtOAc = 1:1); IR
a
b
Inseparable diastereomeric mixtures. Determined by chiral HPLC.
c
d
Results from previous publications. Isolated yield of total isomers.
column chromatography to give thioamide products 7−9, 18−21, and
27 using a gradient solvent mixture eluate.
1
(NaCl) 1491, 1448; H NMR (500 MHz, CDCl3) δ 7.75 (d, J = 7.5
Hz, 2H), 7.65 (d, J = 7.4 Hz, 2H), 7.39 (t, J = 7.4 Hz, 2H), 7.31 (t, J =
7.4 Hz, 2H), 6.46 (s, 1H), 4.37 (d, J = 7.4 Hz, 2H), 4.26 (t, J = 7.3 Hz,
1H), 4.08 (d, J = 4.4 Hz, 2H), 3.87 (t, J = 6.9 Hz, 2H), 3.60 (t, J = 6.8
Hz, 2H), 2.11−2.05 (m, 2H), 1.97 (p, J = 6.9 Hz, 2H); 13C NMR (125
MHz, CDCl3) δ 193.6, 155.9, 143.8, 141.1, 127.5, 127.0, 125.2, 119.8,
67.1, 54.0, 49.5, 48.5, 47.0, 26.0, 23.6; HRMS (ESI) calcd for
C21H23N2O2S (MH+) 367.1475, found 367.1480.
tert-Butyl (2-(Pyrrolidin-1-yl)-2-thioxoethyl)carbamate (19).
Amide 15 (761 mg, 3.34 mmol), Lawesson’s reagent (1640 mg, 4.07
mmol), and sodium bicarbonate (2800 mg, 33.4 mmol) were reacted
and worked up as described above. Product 19: yellow solid, 780 mg,
yield 96%; Rf = 0.30 (hexanes/EtOAc = 2:1); IR (NaCl) 2972, 1716,
1484; 1H NMR (500 MHz, CDCl3) δ 6.09 (s, 1H), 4.01 (d, J = 4.4 Hz,
2H), 3.86 (t, J = 7.0 Hz, 2H), 3.61 (t, J = 6.9 Hz, 2H), 2.11 (p, J = 6.9
Benzyl (2-((2R,5R)-2,5-Dimethylpyrrolidin-1-yl)-2-thioxoethyl)-
carbamate (7). Amide 4 (983 mg, 3.39 mmol), Lawesson’s reagent
(1640 mg, 4.07 mmol), and sodium bicarbonate (2850 mg, 34.0
mmol) were reacted and worked up as described above. Product 22:
yellow solid, 1031 mg, yield 99%; Rf = 0.40 (hexanes/EtOAc = 2:1);
[α]24.7D +79.0 (c 1.26, MeOH); IR (NaCl) 2968, 1719, 1465, 1208; 1H
NMR (500 MHz, CDCl3) δ 7.42−7.26 (m, 5H), 6.35 (br, 1H), 5.19−
5.08 (m, 2H), 4.78 (p, J = 6.6 Hz, 1H), 4.36−4.29 (m, 1H), 4.21 (dd, J
= 16.6, 4.4 Hz, 1H), 4.08 (dd, J = 16.6, 4.8 Hz, 1H), 2.42−2.15 (m,
2H), 1.74 (dd, J = 11.8, 5.4 Hz, 1H), 1.68 (dd, J = 12.0, 5.7 Hz, 1H),
1.35 (d, J = 6.4 Hz, 3H), 1.30 (d, J = 6.4 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 194.4, 155.8, 136.4, 128.3, 127.8, 127.8, 66.7, 59.9,
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Hz, 2H), 1.99 (p, J = 7.0 Hz, 2H), 1.45 (s, 9H); 13C NMR (125 MHz,
CDCl3) δ 194.0, 155.4, 79.5, 53.9, 49.5, 48.4, 28.3, 26.0, 23.7; HRMS
(ESI) calcd for C11H20N2NaO2S (MNa+) 267.1138, found 267.1135.
Allyl (2-(Pyrrolidin-1-yl)-2-thioxoethyl)carbamate (21). Amide 17
(505 mg, 2.38 mmol), Lawesson’s reagent (1150 mg, 2.86 mmol), and
sodium bicarbonate (1999 mg, 23.8 mmol) were reacted and worked
up as described above. Product 21: white solid, 496 mg, yield 95%; Rf
= 0.20 (hexanes/EtOAc = 2:1); IR (NaCl) 1721, 1490; 1H NMR (500
MHz, CDCl3) δ 6.36 (s, 1H), 5.93 (ddd, J = 22.7, 10.8, 5.6 Hz, 1H),
5.32 (dd, J = 17.0, 1.4 Hz, 1H), 5.21 (dt, J = 11.7, 1.2 Hz, 1H), 4.59 (d,
J = 5.5 Hz, 2H), 4.06 (d, J = 4.5 Hz, 2H), 3.85 (t, J = 7.1 Hz, 2H), 3.63
(t, J = 6.9 Hz, 2H), 2.16−2.07 (m, 2H), 2.05−1.95 (m, 2H); 13C NMR
(125 MHz, CDCl3) δ 193.3, 155.5, 132.5, 117.3, 65.5, 53.8, 49.5, 48.4,
25.9, 24.5, 23.5; HRMS (ESI) calcd for C10H17N2O2S (MH+)
229.1005, found 229.1006.
(1.01 mmol) and TEA (87 μL, 0.60 mmol) were reacted and worked
up as described above. Product 10b, major: yellow oil, 92.1 mg, yield
51%; Rf = 0.50 (hexanes/EtOAc = 2:1); [α]23.1 +67.7 (c 1.03,
D
1
MeOH); IR (NaCl) 2970, 1714, 1497, 1456, 1215; H NMR (600
MHz, CDCl3) δ 7.40−7.28 (m, 5H), 6.02 (d, J = 9.8 Hz, 1H), 5.78
(ddd, J = 17.3, 10.0, 8.6 Hz, 1H), 5.10 (dd, J = 32.4, 14.7 Hz, 2H), 5.01
(dd, J = 11.1, 7.6 Hz, 2H), 4.86 (p, J = 6.6 Hz, 1H), 4.69 (t, J = 9.3 Hz,
1H), 4.46 (p, J = 6.6 Hz, 1H), 2.63−2.56 (m, 1H), 2.34 (tt, J = 13.1,
6.7 Hz, 1H), 2.25 (ddd, J = 20.4, 13.5, 6.9 Hz, 1H), 1.80 (dd, J = 12.2,
5.8 Hz, 1H), 1.71 (dd, J = 12.3, 6.1 Hz, 1H), 1.36 (d, J = 3.0 Hz, 3H),
1.35 (d, J = 3.1 Hz, 3H), 0.97 (d, J = 6.8 Hz, 3H); 13C (150 MHz,
CDCl3) δ 199.2, 155.3, 139.1, 136.5, 128.3, 127.9, 127.8, 116.3, 66.6,
60.3, 59.6, 58.4, 46.8, 31.0, 28.3, 21.2, 16.6, 16.1; HRMS (ESI) calcd
for C20H29N2O2S (MH+) 361.1944, found 361.1943.
Benzyl (2R,3R)-1-((2R,5R)-2,5-Dimethylpyrrolidin-1-yl)-3-methyl-
1-thioxopent-4-en-2-ylcarbamate (10b, minor). Compound 7
(154 mg, 0.50 mmol), FeBr3 (30 mg, 0.10 mmol), allylic bromide
(1.01 mmol) and TEA (87 μL, 0.60 mmol) were reacted and worked
up as described above. Product 10b, minor: yellow oil, 11.4 mg, yield
tert-Butyl (2-((2S,5S)-2,5-Diphenylpyrrolidin-1-yl)-2-thioxoethyl)-
carbamate (27). Amide 26 (1216 mg, 3.20 mmol), Lawesson’s
reagent (751 mg, 1.86 mmol), and sodium bicarbonate (1550 mg, 3.84
mmol) were reacted and worked up as described above. Product 27:
light yellow solid, 945 mg, yield 75%; Rf = 0.40 (hexanes/EtOAc =
6%; Rf = 0.55 (hexanes/EtOAc = 2:1); [α]24.9 +100.3 (c 0.44,
D
3:1); [α]24.7 −12.9 (c 1.39, MeOH); IR (NaCl) 1709.47, 1447.44,
1
MeOH); IR (NaCl) 2970, 1714, 1497, 1456, 1215; H NMR (600
D
1
1165.50; H NMR (600 MHz, CDCl3) δ 7.44−7.10 (m, 10H), 6.04
MHz, CDCl3) δ 7.40−7.27 (m, 5H), 6.14 (d, J = 9.7 Hz, 1H), 5.66
(ddd, J = 17.3, 10.3, 8.0 Hz, 1H), 5.17−4.98 (m, 4H), 4.83−4.78 (m,
1H), 4.65 (t, J = 9.5 Hz, 1H), 4.35 (p, J = 6.6 Hz, 1H), 2.65−2.56 (m,
1H), 2.32−2.17 (m, 2H), 1.74 (dd, J = 11.8, 5.4 Hz, 1H), 1.66 (dd, J =
11.7, 5.4 Hz, 1H), 1.33 (d, J = 6.6 Hz, 3H), 1.31 (d, J = 6.4 Hz, 3H),
1.13 (d, J = 6.8 Hz, 3H); 13C (150 MHz, CDCl3) δ 199.2, 155.5,
138.0, 136.4, 128.4, 128.0, 127.9, 116.4, 66.7, 60.6, 59.6, 58.5, 46.5,
30.8, 28.5, 21.2, 16.5, 15.9; HRMS (ESI) calcd for C20H29N2O2S
(MH+) 361.1944, found 361.1943.
(d, J = 8.4 Hz, 1H), 5.83 (s, 1H), 5.70 (d, J = 8.1 Hz, 1H), 4.28 (dd, J
= 17.2, 4.5 Hz, 1H), 3.44 (d, J = 17.2 Hz, 1H), 2.69−2.62 (m, 1H),
2.53 (tdd, J = 14.1, 8.4, 6.0 Hz, 1H), 1.90 (dd, J = 12.4, 5.9 Hz, 1H),
1.84 (dd, J = 12.5, 6.0 Hz, 1H), 1.40 (s, 9H); 13C NMR (150 MHz,
CDCl3) δ 198.3, 155.5, 141.2, 140.6, 129.2, 128.5, 127.8, 126.8, 125.4,
125.1, 79.5, 68.6, 68.6, 65.9, 65.8, 49.3, 32.9, 30.0, 28.3, 28.2; HRMS
(ESI) calcd for C23H28N2NaO2S (MNa+) 419.1764, found 419.1757.
General Procedure for the Preparation of Compounds 10−
12. Thioamide (1.00 mmol), FeBr3 (45 mg, 0.20 mmol), and allylic
bromide (2.00 mmol) were dissolved in a minimum amount of dry
MeCN (about 1 mL) in a 25 mL pear-shaped flask at ambient
temperature under argon atmosphere. The mixture was stirred at 45−
50 °C for 24−48 h. Dry THF (15 mL) was added to dilute the
reaction and the mixture cooled to −78 °C. TEA (173 μL, 1.20 mmol)
was added slowly to the reaction mixture, and the mixture was allowed
to warm slowly to ambient temperature and then heated slowly to 45
°C for completion. The reaction was quenched by the addition of a
saturated ammonium chloride solution (1 mL), and the volatiles were
removed under reduced pressure; the residue was extracted twice with
hexanes and diethyl ether. The combined organic layers were washed
with a saturated ammonium chloride solution (10 mL × 1) and a
saturated sodium bicarbonate solution (10 mL × 1) and dried over
anhydrous MgSO4. The dry solution was filtered and concentrated
under reduced pressure, and the crude product was purified by flash
column chromatography to afford compounds 10−12 using a gradient
solvent mixture eluate.
(S)-Methyl 2-((S)-1-(Benzyloxycarbonylamino)-2-((2R,5R)-2,5-di-
methylpyrrolidin-1-yl)-2-thioxoethyl)but-3-enoate (10c). Com-
pound 7 (75.5 mg, 0.25 mmol), FeBr3 (15 mg, 0.05 mmol), allylic
bromide (0.62 mmol), and TEA (43 μL, 0.30 mmol) were reacted and
worked up as described above. Product 10c: yellow oil, 86 mg, yield
86%; Rf = 0.40 (hexanes/EtOAc = 2:1); [α]25.0 −0.3 (c 0.64,
D
1
MeOH); IR (NaCl) 1729, 1498, 1464, 1196; H NMR (500 MHz,
CDCl3) δ 7.45−7.24 (m, 5H), 5.88−5.80 (m, 2H), 5.30−4.94 (m,
5H), 4.85−4.72 (m, 2H), 3.77−3.64 (m, 1H), 3.61 (s, 3H), 2.39−2.16
(m, 2H), 1.75 (dd, J = 12.3, 5.9 Hz, 1H), 1.67 (dd, J = 12.3, 6.1 Hz,
1H), 1.30 (d, J = 6.6 Hz, 3H), 1.23 (d, J = 6.4 Hz, 3H); 13C (150
MHz, CDCl3) δ 196.6, 171.7, 154.9, 136.3, 132.0, 128.3, 127.9, 127.8,
121.0, 66.7, 59.8, 59.6, 58.6, 57.0, 51.9, 30.9, 28.5, 21.4, 16.0; HRMS
(ESI) calcd for C21H29N2O4S (MH+) 405.1843, found 405.1836.
HPLC analysis: de >99%. Chiralpak AD-RH column (CH3CN/H2O
55/45, 0.5 mL/min, 254 nm); retention times of the only
diastereomer observed: 12.8 min (10c).
(S)-Ethyl 2-((S)-1-(Benzyloxycarbonylamino)-2-((2R,5R)-2,5-dime-
thylpyrrolidin-1-yl)-2-thioxoethyl)but-3-enoate (10d). Compound 7
(127 mg, 0.42 mmol), FeBr3 (25 mg, 0.08 mmol), allylic bromide
(0.83 mmol), and TEA (72 μL, 0.50 mmol) were reacted and worked
up as described above. Product 10d: yellow oil, 144 mg, yield 83%; Rf
(S)-Ethyl 4-(Benzyloxycarbonylamino)-5-((2R,5R)-2,5-dimethyl-
pyrrolidin-1-yl)-2-methylene-5-thioxopentanoate (10a, major).
Compound 7 (82 mg, 0.27 mmol), FeBr3 (16 mg, 0.05 mmol), allylic
bromide (0.53 mmol), and TEA (46 μL, 0.32 mmol) were reacted and
worked up as described above. Product 10a, major + minor: yellow
oil, 71 mg, yield 64%; Rf = 0.45 (hexanes/EtOAc = 2: 1); IR (NaCl)
1717, 1461, 1134; 1H NMR (500 MHz, CDCl3) δ 7.41−7.21 (m, 5H),
6.15 (s, 1H), 6.11 (d, J = 9.5 Hz, 1H), 5.63 (s, 1H), 5.20−5.07 (m,
2H), 4.97 (d, J = 12.3 Hz, 1H), 4.83−4.75 (m, 1H), 4.71−4.63 (m,
1H), 4.25 (q, J = 7.1 Hz, 2H), 2.62 (dd, J = 13.3, 3.7 Hz, 1H), 2.44
(dd, J = 13.3, 9.7 Hz, 1H), 2.39−2.16 (m, 2H), 1.79 (dd, J = 12.0, 5.7
Hz, 1H), 1.69 (dd, J = 12.2, 5.9 Hz, 1H), 1.37 (d, J = 6.4 Hz, 3H), 1.32
(dd, J = 13.4, 6.6 Hz, 6H); 13C (125 MHz, CDCl3) δ 199.3, 166.6,
155.4, 136.4, 135.3, 128.7, 128.3, 127.8, 127.8, 66.6, 60.9, 59.4, 57.8,
55.4, 41.8, 31.1, 28.5, 21.6, 16.6, 14.2; HRMS (ESI) calcd for
C22H31N2O4S (MH+) 419.1995, found 419.1993. HPLC analysis: de
=56%. Chiralpak AD-RH column (CH3CN/H2O 50/50 to 75/25, in
30 min, 0.4 mL/min, 254 nm); retention times of the diastereomers
observed: 14.3 min, 15.9 min (10a).
= 0.50 (hexanes/EtOAc = 2:1); [α]24.7 +20.0 (c 1.26, MeOH); IR
D
(NaCl) 2974, 1726, 1464, 1184; 1H NMR (600 MHz, CDCl3) δ
7.40−7.27 (m, 5H), 5.88−5.79 (m, 2H), 5.28−4.98 (m, 4H), 4.86−
4.76 (m, 2H), 4.10−4.01 (m, 2H), 3.69 (t, J = 9.4 Hz, 1H), 2.38−2.30
(m, 1H), 2.22 (ddd, J = 20.4, 13.4, 6.9 Hz, 1H), 1.75 (dd, J = 12.3, 6.0
Hz, 1H), 1.67 (dd, J = 12.4, 6.2 Hz, 1H), 1.30 (d, J = 6.6 Hz, 3H),
1.26−1.17 (m, 6H); 13C (150 MHz, CDCl3) δ 196.7, 171.3, 155.0,
136.3, 132.1, 128.3, 128.0, 127.9, 120.9, 66.7, 60.9, 59.9, 59.6, 58.6,
56.9, 30.9, 28.5, 21.4, 16.0, 14.0; HRMS (ESI) calcd for
C22H30N2NaO4S (MNa+) 441.1818, found 441.1811. HPLC analysis:
de >99%. Chiralpak AD-RH column (CH3CN/H2O 55/45, 0.5 mL/
min, 254 nm); retention times of the only diastereomer observed: 15.3
min (10d).
(S)-Ethyl 4-(((Benzyloxy)carbonyl)amino)-5-((2S,5S)-2,5-bis-
(methoxymethyl)pyrrolidin-1-yl)-2-methylene-5-thioxopentanoate
(11a). Compound 8 (70 mg, 0.19 mmol), FeBr3 (23 mg, 0.08 mmol),
allylic bromide (0.38 mmol), and TEA (40 μL, 0.27 mmol) were
reacted and worked up as described above. Product 11a: clear oil, 47
Benzyl (2S,3S)-1-((2R,5R)-2,5-dimethylpyrrolidin-1-yl)-3-methyl-
1-thioxopent-4-en-2-ylcarbamate (10b, major). Compound 7
(154 mg, 0.50 mmol), FeBr3 (30 mg, 0.10 mmol), allylic bromide
1295
dx.doi.org/10.1021/jo201753q | J. Org. Chem. 2012, 77, 1289−1300

The Journal of Organic Chemistry
Article
mg, yield 54%; Rf = 0.40 (hexanes/EtOAc = 2:1); [α]24.8 +64.3 (c
0.10, MeOH); IR (NaCl) 1716, 1500, 1447, 1115; H NMR (500
(S)-Methyl 2-((S)-1-(Benzyloxycarbonylamino)-2-((2S,5S)-2,5-di-
phenylpyrrolidin-1-yl)-2-thioxoethyl)but-3-enoate (12c). Compound
9 (200 mg, 0.47 mmol), FeBr3 (30 mg, 0.10 mmol), allylic bromide
(112 μL, 0.94 mmol), and TEA (82 μL, 0.57 mmol) were reacted and
worked up as described above. Product 12c: yellow oil, 173 mg, yield
D
1
MHz, CDCl3) δ 7.40−7.24 (m, 5H), 6.17 (s, 1H), 6.08 (d, J = 9.5 Hz,
1H), 5.63 (s, 1H), 5.26−4.97 (m, 3H), 4.80 (t, J = 8.5 Hz, 1H), 4.68
(td, J = 7.8, 3.8 Hz, 1H), 4.28−4.20 (m, 2H), 3.72−3.62 (m, 2H),
3.58−3.51 (m, 1H), 3.42 (dd, J = 17.4, 8.7 Hz, 1H), 3.32 (t, J = 10.4
Hz, 6H), 2.64 (dd, J = 13.4, 3.7 Hz, 1H), 2.43 (dd, J = 13.3, 9.8 Hz,
1H), 2.31 (ddd, J = 19.8, 12.3, 7.4 Hz, 1H), 2.11 (dddd, J = 35.1, 19.3,
12.6, 6.9 Hz, 3H), 1.35−1.30 (m, 3H); 13C NMR (125 MHz, CDCl3)
δ 201.92, 166.61, 155.36, 136.52, 135.38, 128.76, 128.37, 127.95,
127.90, 99.95, 73.14, 69.21, 66.59, 62.89, 61.27, 61.00, 58.99, 58.90,
56.16, 42.06, 27.57, 25.44, 14.15; HRMS (ESI) calcd for C24H35N2O6S
(MH+) 479.2210, found 479.2211. HPLC analysis: de = 90%.
Chiralpak AD-RH column (CH3CN/H2O 60/40 to 70/30, in 30
min, 0.5 mL/min, 254 nm); retention times of the diastereomeric
mixture observed: 8.8 min (11a) and 14.3.
63%; Rf = 0.50 (hexanes/EtOAc = 2:1); [α]24.5 +126.0 (c 0.55,
D
1
MeOH); IR (NaCl) 3029, 2950, 1728, 1447; H NMR (500 MHz,
CDCl3) δ 7.41−7.10 (m, 15H), 6.23 (d, J = 7.9 Hz, 1H), 5.91 (d, J =
8.6 Hz, 1H), 5.75−5.66 (m, 1H), 5.27 (d, J = 9.4 Hz, 1H), 5.17−5.04
(m, 2H), 4.72 (d, J = 12.3 Hz, 1H), 4.57 (d, J = 12.3 Hz, 1H), 3.76 (t, J
= 9.4 Hz, 1H), 3.68 (s, 3H), 2.83−2.70 (m, 1H), 2.46 (tt, J = 16.2, 8.8
Hz, 1H), 1.91 (dd, J = 12.5, 5.8 Hz, 1H), 1.75 (dd, J = 12.6, 6.0 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ 200.2, 172.5, 153.5, 141.5,
141.2, 136.3, 131.7, 128.4, 128.2, 128.1, 127.7, 127.7, 127.2, 126.7,
125.5, 125.5, 120.8, 68.8, 67.0, 66.2, 58.9, 57.0, 52.0, 32.9, 30.1; HRMS
(ESI) calcd for C31H33N2O4S (MH+) 529.2156, found 529.2164.
HPLC analysis: de >99%. Chiralpak AD-RH column (CH3CN/H2O
60/40, 0.5 mL/min, 254 nm); retention times of the only
diastereomer observed: 19.7 min (12c).
Benzyl (2S,3S)-1-((2S,5S)-2,5-Bis(methoxymethyl)pyrrolidin-1-yl)-
3-methyl-1-thioxopent-4-en-2-ylcarbamate13C (11b). Compound 8
(90 mg, 0.25 mmol), FeBr3 (30 mg, 0.10 mmol), crotyl bromide (0.49
mmol), and TEA (50 μL, 0.34 mmol) were reacted and worked up as
described above. Product 11b: yellow oil, 54 mg, yield 52%; Rf = 0.60
(S)-ethyl 2-((S)-1-(benzyloxycarbonylamino)-2-((2S,5S)-2,5-diphe-
nylpyrrolidin-1-yl)-2-thioxoethyl)but-3-enoate (12d). Compound 9
(124 mg, 0.29 mmol), FeBr3 (19 mg, 0.06 mmol), allylic bromide (78
μL, 0.58 mmol), and TEA (51 μL, 0.35 mmol) were reacted and
worked up as described above. Product 12d: yellow oil, 109 mg, yield
(hexanes/EtOAc = 2:1); [α]24.1 +40.8 (c 0.34, MeOH); IR (NaCl)
D
1
1792, 1498, 1455, 1199, 1113; H NMR (500 MHz, CDCl3) δ 7.42−
7.22 (m, 5H), 5.99 (d, J = 9.7 Hz, 1H), 5.83−5.72 (m, 1H), 5.15−4.98
(m, 1H), 4.83 (t, J = 5.6 Hz, 4H), 4.76−4.72 (m, 1H), 4.37 (td, J = 8.2,
3.5 Hz, 1H), 3.82 (dd, J = 9.4, 5.8 Hz, 1H), 3.63 (dd, J = 9.4, 2.6 Hz,
1H), 3.54 (dd, J = 9.7, 3.6 Hz, 1H), 3.30 (s, 7H), 2.61−2.52 (m, 1H),
2.39−2.22 (m, 1H), 2.10 (dddd, J = 31.9, 25.2, 12.5, 7.1 Hz, 3H), 0.99
(d, J = 6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 201.5, 155.2,
138.9, 136.5, 128.3, 127.8, 127.8, 116.3, 72.7, 69.5, 66.6, 63.0, 62.0,
61.0, 58.9, 58.7, 46.5, 27.7, 25.4, 16.3; HRMS(ESI) calcd for
C22H33N2O4S (MH+) 421.2156, found 421.2152. HPLC analysis: de
= 88%. Chiralpak AD-RH column (CH3CN/H2O 30/70, 0.5 mL/min,
254 nm); the diastereomeric mixture: 19.5 min, 21.6 min (11b).
(S)-Methyl 2-((S)-1-(Benzyloxycarbonylamino)-2-((2S,5S)-2,5-bis-
(methoxymethyl)pyrrolidin-1-yl)-2-thioxoethyl)but-3-enoate (11c).
Compound 8 (102 mg, 0.28 mmol), FeBr3 (30 mg, 0.10 mmol),
allylic bromide (0.56 mmol), and TEA (55 μL, 0.38 mmol) were
reacted and worked up as described above. Product 11c: yellow oil, 83
70%; Rf = 0.55 (hexanes/EtOAc = 3:1); [α]24.8 +127.0 (c 1.05,
D
MeOH); IR (NaCl) 1718, 1448, 1187; 1H NMR (500 MHz, CDCl3) δ
7.45−7.08 (m, 15H), 6.24 (d, J = 8.0 Hz, 1H), 5.91 (d, J = 8.6 Hz,
1H), 5.75−5.65 (m, 1H), 5.28 (d, J = 9.5 Hz, 1H), 5.17−5.04 (m,
2H), 4.73 (d, J = 12.3 Hz, 1H), 4.57 (d, J = 12.3 Hz, 1H), 4.31−4.01
(m, 2H), 3.74 (t, J = 9.4 Hz, 1H), 2.81−2.69 (m, 1H), 2.54−2.39 (m,
1H), 1.91 (dd, J = 12.5, 5.8 Hz, 1H), 1.75 (dd, J = 12.6, 6.0 Hz, 1H),
1.24−1.18 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 200.3, 172.1,
153.5, 141.5, 141.2, 136.3, 131.9, 128.4, 128.2, 128.1, 127.8, 127.7,
127.2, 126.7, 125.5, 120.7, 68.9, 67.0, 66.2, 60.9, 59.0, 57.0, 33.0, 30.1,
14.0; HRMS (ESI) calcd for C32H35N2O4S (MH+) 543.2312, found
543.2310. HPLC analysis: de >99%. Chiralpak AD-RH column
(CH3CN/H2O 60/40, 0.5 mL/min, 254 nm); retention times of the
only diastereomer observed: 21.2 min (12d).
tert-Butyl 3-Methyl-1-(pyrrolidin-1-yl)-1-thioxopent-4-en-2-ylcar-
bamate (23a). Compound 19 (127 mg, 0.56 mmol), FeBr3 (20 mg,
0.06 mmol), crotyl bromide (168 μL, 1.40 mmol), and TEA (96 μL,
0.67 mmol) were reacted and worked up as described above. Product
23a: yellow oil, 105 mg, yield 63%; Rf = 0.65 (hexanes/EtOAc = 2:1);
mg, yield 64%; Rf = 0.45 (hexanes/EtOAc = 2:1); [α]24.3 −21.8 (c
D
0.32, MeOH); IR (NaCl) 1729, 1451; 1H NMR (500 MHz, CDCl3) δ
7.40−7.23 (m, 5H), 5.90 (d, J = 9.9 Hz, 1H), 5.83 (dt, J = 17.0, 9.7 Hz,
1H), 5.21 (dt, J = 16.8, 7.0 Hz, 3H), 5.07 (s, 2H), 4.82 (td, J = 7.5, 2.7
Hz, 1H), 4.73 (td, J = 7.8, 4.2 Hz, 1H), 3.64 (s, 3H), 3.46−3.38 (m,
2H), 3.32 (s, 3H), 3.25 (s, 3H), 2.31−2.20 (m, 1H), 2.17−1.99 (m,
3H); 13C NMR (125 MHz, CDCl3) δ 199.4, 171.3, 154.9, 136.4,
131.8, 128.4, 128.0, 127.9, 121.0, 72.9, 68.7, 66.8, 62.9, 62.1, 59.9, 58.8,
58.6, 57.5, 52.0, 27.3, 25.1; HRMS (ESI) calcd for C23H33N2O6S
(MH+) 465.2054, found 465.2052. HPLC analysis: de >99%.
Chiralpak AD-RH column (CH3CN/H2O 50/50, 0.5 mL/min, 254
nm); retention times of the only diastereomer observed: 21.4 min
(11c).
1
IR (NaCl) 2974, 1710, 1487, 1165; H NMR (500 MHz, CDCl3) δ
5.82 (ddd, J = 17.2, 10.3, 8.1 Hz, 1H), 5.44 (d, J = 9.6 Hz, 1H), 5.09
(ddd, J = 11.3, 9.1, 3.6 Hz, 2H), 4.56 (dd, J = 11.6, 6.9 Hz, 1H), 4.06−
3.99 (m, 1H), 3.94−3.78 (m, 2H), 3.75−3.67 (m, 1H), 2.74−2.62 (m,
1H), 2.16−1.86 (m, 4H), 1.41 (s, 9H), 0.99 (d, J = 6.8 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 199.9, 155.2, 139.2, 116.1, 79.4, 60.2, 53.7,
51.0, 44.3, 28.3, 26.0, 23.9, 16.8; HRMS (ESI) calcd for C15H27N2O2S
(MH+) 299.1788, found 299.1788.
Ethyl 2-(1-(tert-Butoxycarbonylamino)-2-(pyrrolidin-1-yl)-2-
thioxoethyl)but-3-enoate (23c). Compound 19 (167 mg, 0.68
mmol), FeBr3 (25 mg, 0.07 mmol), allylic bromide (198 μL, 1.47
mmol), and TEA (108 μL, 0.75 mmol) were reacted and worked up as
described above. Product 23c: yellow oil, 183 mg, yield 79%; Rf = 0.60
(hexanes/EtOAc = 2: 1); IR (NaCl) 2978, 1724, 1168; 1H NMR (500
MHz, CDCl3) δ 5.82 (d, J = 16.9 Hz, 1H), 5.35−5.24 (m, 2H), 5.22−
5.09 (m, 2H), 4.14−4.04 (m, 3H), 4.04−3.97 (m, 1H), 3.87 (t, J = 9.3
Hz, 1H), 3.82−3.71 (m, 2H), 2.15−1.89 (m, 4H), 1.40 (s, 9H), 1.21
(t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 197.2, 171.6,
154.8, 132.1, 120.5, 79.9, 60.9, 56.9, 56.2, 53.8, 51.2, 28.2, 25.9, 24.0,
14.0; HRMS (ESI) calcd for C17H29N2O4S (MH+) 357.1843, found
357.1844.
(S)-Ethyl 2-((S)-1-(Benzyloxycarbonylamino)-2-((2S,5S)-2,5-bis-
(methoxymethyl)pyrrolidin-1-yl)-2-thioxoethyl)but-3-enoate (11d).
Compound 8 (88 mg, 0.24 mmol), FeBr3 (30 mg, 0.10 mmol), allylic
bromide (0.73 mmol) and TEA (50 μL, 0.34 mmol) were reacted and
worked up as described above. Product 11d: yellow oil, 75 mg, yield
65%; Rf = 0.55 (hexanes/EtOAc = 2:1); [α]23.7 −24.2 (c 0.61,
D
MeOH); IR (NaCl) 1726, 1115; 1H NMR (500 MHz, CDCl3) δ
7.39−7.26 (m, 5H), 5.93−5.80 (m, 2H), 5.27−5.16 (m, 2H), 5.09−
5.05 (m, 2H), 4.82 (dd, J = 7.4, 4.6 Hz, 1H), 4.75 (dd, J = 11.7, 7.9 Hz,
1H), 4.23−4.02 (m, 2H), 3.69−3.59 (m, 2H), 3.47−3.21 (m, 8H),
2.24 (dd, J = 16.8, 9.6 Hz, 1H), 2.18−1.84 (m, 3H), 1.24 (t, J = 7.1 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 199.3, 170.9, 154.8, 136.3,
131.8, 128.3, 128.0, 127.9, 120.9, 72.9, 68.7, 66.8, 62.9, 62.0, 61.0, 60.0,
58.8, 58.6, 57.5, 27.3, 25.0, 14.0; HRMS (ESI) calcd for C24H35N2O6S
(MH+) 479.2210, found 479.2208. HPLC analysis: de >99%.
Chiralpak AD-RH column (CH3CN/H2O 50/50, 0.5 mL/min, 254
nm); retention times of the only diastereomer observed: 17.0 min
(11d).
Benzyl 1-(Cyclohex-2-enyl)-2-(pyrrolidin-1-yl)-2-thioxoethylcar-
bamate (24b). Compound 20 (180 mg, 0.79 mmol), FeBr3 (48 mg,
0.16 mmol), allylic bromide (181 μL, 1.57 mmol), and TEA (137 μL,
0.95 mmol) were reacted and worked up as described above. Product
24b: yellow oil, 34 mg, yield 15%; Rf1= 0.40 (hexanes/EtOAc = 3:1);
IR (NaCl) 2924, 1717, 1489, 1450; H NMR (500 MHz, CDCl3) δ
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7.41−7.22 (m, 5H), 5.86−5.77 (m, 2H), 5.34 (d, J = 8.0 Hz, 1H),
5.15−5.10 (m, 1H), 5.04 (d, J = 12.3 Hz, 1H), 4.65 (t, J = 9.8 Hz, 1H),
3.94−3.70 (m, 3H), 2.56 (s, 1H), 2.12−1.91 (m, 6H), 1.83−1.53 (m,
4H); 13C NMR (125 MHz, CDCl3) δ 206.3, 199.5, 156.0, 136.3,
130.7, 128.4, 128.0, 127.8, 125.9, 66.8, 60.2, 53.6, 51.2, 41.4, 25.9, 25.3,
24.8, 24.0, 20.2; HRMS (ESI) calcd for C20H27N2O2S (MH+)
359.1788, found 359.1788.
Benzyl ((2S,3S)-3-(Diethylcarbamoyl)-1-(pyrrolidin-1-yl)-1-thioxo-
pent-4-en-2-yl)carbamate (24c). Compound 20 (81 mg, 0.29 mmol),
FeBr3 (36 mg, 0.12 mmol), allylic bromide (0.59 mmol), and TEA (60
μL, 0.41 mmol) were reacted and worked up as described above.
Product 24b: yellow oil, 63 mg, yield 51%; Rf = 0.65 (hexanes/EtOAc
= 1: 2); IR (NaCl) 2974, 1720, 1626; 1H NMR (500 MHz, CDCl3) δ
7.39−7.27 (m, 5H), 5.94−5.82 (m, 1H), 5.40 (d, J = 10.3 Hz, 1H),
5.29−4.99 (m, 5H), 4.34−4.26 (m, 1H), 4.01 (dt, J = 13.0, 8.0 Hz,
2H), 3.81−3.43 (m, 4H), 3.39−3.13 (m, 3H), 2.12−1.85 (m, 4H),
1.21 (t, J = 7.1 Hz, 3H), 1.02 (t, J = 7.0 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 197.05, 170.10, 155.55, 136.21, 133.95, 128.41,
128.04, 127.88, 119.94, 114.67, 66.95, 57.85, 54.38, 53.82, 51.55,
42.56, 40.69, 25.94, 24.10, 14.37, 12.69; HRMS (ESI) calcd for
C22H32N3O3S (MH+) 418.2159, found 418.2166.
1H), 1.72−1.62 (m, 3H); 13C NMR (150 MHz, CDCl3) δ 197.1,
155.9, 132.4, 131.3, 125.7, 117.9, 66.1, 50.5, 39.6, 29.4, 24.6, 19.8;
HRMS (ESI) calcd for C16H25N2O2S (MH+) 309.1631, found
309.1629.
2-Oxo-2-phenylethyl 2-(1-(((Allyloxy)carbonyl)amino)-2-(pyrroli-
din-1-yl)-2-thioxoethyl)but-3-enoate (25e). Compound 21 (194 mg,
0.85 mmol), FeBr3 (77 mg, 0.34 mmol), allylic bromide (283 mg, 1.70
mmol), and TEA (147 μL, 1.02 mmol) were reacted and worked up as
described above. Product 25d: yellow oil, 186 mg, yield 51%; Rf = 0.50
(hexanes/EtOAc = 2:1); IR (NaCl) 2925, 1716; 1H NMR (500 MHz,
CDCl3) δ 7.96−7.81 (m, 2H), 7.63−7.55 (m, 1H), 7.47 (dd, J = 10.7,
4.8 Hz, 2H), 5.98−5.82 (m, 2H), 5.56 (d, J = 10.1 Hz, 1H), 5.48−5.14
(m, 7H), 4.54 (ddd, J = 34.0, 13.4, 5.5 Hz, 1H), 4.11 (t, J = 9.5 Hz,
1H), 4.03 (t, J = 6.8 Hz, 2H), 3.91 (dt, J = 13.3, 6.6 Hz, 1H), 3.81 (dt,
J = 14.2, 7.2 Hz, 1H), 2.08−1.91 (m, 4H). 13C NMR (125 MHz,
CDCl3) δ 196.44, 191.16, 170.89, 155.36, 133.91, 133.77, 132.37,
131.56, 128.75, 127.64, 121.39, 117.57, 66.59, 65.78, 56.53, 56.27,
53.98, 51.35, 25.86, 23.91; HRMS (ESI) calcd for C22H27N2O5S
(MH+) 431.1635, found 431.1632.
General Procedure for the Preparation of Compounds 28−
32. LDA was prepared freshly in a 25 mL flask at 0 °C under argon
atmosphere by mixing diisopropylamine (140 μL, 1.0 mmol) with n-
butyllithium (1.6 M in hexanes, 0.63 mL, 1.0 mmol) in dry THF (10
mL) for 15 min. Then the LDA solution was transferred into a 50-mL
flask which had thioamide 4−6, 19, 20, or 27 (0.33 mmol) dissolved in
dry THF (10 mL) at −78 °C. The mixture was stirred for 30 min at
−78 °C before HMPA (180 μL, 1.0 mmol) was added and another 5
min before the allylic bromide (0.66 mmol) was added, respectively.
The reaction was allowed to warm slowly to room temperature (or
other temperatures found in Table 1) over a period of 4 h. Then the
reaction was quenched by the addition of a saturated ammonium
chloride solution (1 mL). THF was removed under reduced pressure;
the residue was extracted twice with hexanes and diethyl ether. The
combined organic layers were pooled and washed with a saturated
sodium bicarbonate solution (10 mL × 1) and a saturated ammonium
chloride solution (10 mL × 1) and dried over anhydrous MgSO4. The
dry solution was concentrated under reduced pressure, and the crude
product was purified by flash column chromatography to afford C-
allylation compounds 28−32.
Allyl 3-Methyl-1-(pyrrolidin-1-yl)-1-thioxopent-4-en-2-ylcarba-
mate (25a). Compound 21 (94 mg, 0.41 mmol), FeBr3 (25 mg,
0.08 mmol), crotyl bromide (107 μL, 0.83 mmol), and TEA (71 μL,
0.49 mmol) were reacted and worked up as described above. Product
25a: yellow oil, 92 mg, yield 80%; Rf = 0.50 (hexanes/EtOAc = 2:1);
1
IR (NaCl) 2973, 1716, 1495; H NMR (500 MHz, CDCl3) δ 5.87
(dtdd, J = 25.2, 18.2, 10.4, 6.8 Hz, 2H), 5.68 (d, J = 9.6 Hz, 1H),
5.34−5.06 (m, 4H), 4.63−4.47 (m, 3H), 4.10−4.03 (m, 1H), 3.94−
3.80 (m, 2H), 3.78−3.70 (m, 1H), 2.78−2.68 (m, 1H), 2.15−1.91 (m,
4H), 1.01 (d, J = 6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 199.4,
155.6, 139.0, 132.5, 117.4, 116.3, 65.6, 60.6, 53.8, 51.1, 44.0, 26.0, 23.9,
16.7; HRMS (ESI) calcd for C14H23N2O2S (MH+) 283.1475, found
283.1471.
Allyl 3,3-Dimethyl-1-(pyrrolidin-1-yl)-1-thioxopent-4-en-2-ylcar-
bamate (25b). Compound 21 (138 mg, 0.60 mmol), FeBr3 (35 mg,
0.12 mmol), allylic bromide (140 μL, 1.20 mmol), and TEA (104 μL,
0.72 mmol) were reacted and worked up as described above. Product
25b: yellow oil, 90 mg, yield 51%; Rf = 0.60 (hexanes/EtOAc = 2:1);
IR (NaCl) 2969, 1721, 1218; 1H NMR (500 MHz, CDCl3) δ 6.00 (dd,
J = 17.8, 10.5 Hz, 1H), 5.90 (tt, J = 13.1, 5.6 Hz, 2H), 5.30 (dd, J =
17.2, 1.4 Hz, 1H), 5.19 (ddd, J = 8.0, 6.8, 1.4 Hz, 1H), 5.10−5.03 (m,
2H), 4.71 (d, J = 10.0 Hz, 1H), 4.62−4.46 (m, 2H), 3.95−3.84 (m,
2H), 3.75 (tt, J = 13.7, 6.7 Hz, 2H), 2.09−1.88 (m, 4H), 1.17 (s, 3H),
1.14 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 198.0, 156.0, 143.5,
132.6, 117.5, 113.3, 65.7, 62.5, 53.7, 51.8, 41.6, 26.0, 24.4, 23.9, 23.5;
HRMS (ESI) calcd for C15H25N2O2S (MH+) 297.1631, found
297.1628.
Ethyl 2-(1-(Allyloxycarbonylamino)-2-(pyrrolidin-1-yl)-2-
thioxoethyl)but-3-enoate (25c). Compound 21 (110 mg, 0.48
mmol), FeBr3 (30 mg, 0.10 mmol), allylic bromide (173 μL, 0.96
mmol), and TEA (84 μL, 0.58 mmol) were reacted and worked up as
described above. Product 25c: yellow oil, 135 mg, yield 82%; Rf = 0.60
(hexanes/EtOAc = 2:1); IR (NaCl) 1725, 1504, 1451; 1H NMR (500
MHz, CDCl3) δ 5.94−5.76 (m, 2H), 5.41 (d, J = 10.2 Hz, 1H), 5.37−
5.10 (m, 5H), 4.53 (ddd, J = 33.6, 13.3, 5.5 Hz, 2H), 4.19−4.00 (m,
4H), 3.90 (t, J = 9.5 Hz, 1H), 3.78 (dtt, J = 21.1, 14.0, 7.0 Hz, 2H),
2.15−1.91 (m, 4H), 1.21 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 197.0, 171.5, 155.4, 132.4, 131.9, 120.9, 117.6, 65.8, 61.0,
56.6, 56.6, 53.8, 51.3, 25.9, 24.0, 13.9; HRMS (ESI) calcd for
C16H25N2O4S (MH+) 341.1530, found 341.1530.
(E)-Benzyl 5-Phenyl-1-(pyrrolidin-1-yl)-1-thioxopent-4-en-2-ylcar-
bamate (31). Thioamide 20 (113 mg, 0.41 mmol), n-butyllithium (1.6
M in hexanes, 0.56 mL, 0.89 mmol), and cinnamyl bromide (72 μL,
0.48 mmol) were reacted and worked up as described above. Product
31: light yellow solid, 118 mg, yield 74%; Rf = 0.50 (hexanes/EtOAc =
1
2:1); IR (NaCl) 1715, 1491, 1449; H NMR (500 MHz, CDCl3) δ
7.38−7.13 (m, 10H), 6.47 (d, J = 15.8 Hz, 1H), 6.17−6.09 (m, 1H),
6.02 (d, J = 9.1 Hz, 1H), 5.11 (d, J = 12.3 Hz, 1H), 5.02 (d, J = 12.2
Hz, 1H), 4.89 (dd, J = 15.9, 7.4 Hz, 1H), 3.87 (dd, J = 13.0, 6.3 Hz,
2H), 3.82−3.75 (m, 1H), 3.70−3.63 (m, 1H), 2.66 (t, J = 7.2 Hz, 2H),
2.11−1.82 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 199.0, 155.5,
136.9, 136.2, 133.6, 128.4, 128.3, 127.9, 127.8, 127.3, 126.0, 124.0,
66.8, 56.9, 53.9, 50.9, 40.0, 26.0, 23.8; HRMS (ESI) calcd for
C23H27N2O2S (MH+) 395.1788, found 395.1787.
(E)-tert-Butyl 5-Phenyl-1-(pyrrolidin-1-yl)-1-thioxopent-4-en-2-yl-
carbamate (32). Thioamide 19 (133 mg, 0.55 mmol), n-butyllithium
(1.6 M in hexanes, 0.75 mL, 1.2 mmol), and cinnamyl bromide (121
μL, 0.82 mmol) were reacted and worked up as described above.
Product 32: yellow oil, 128 mg, yield 65%; Rf = 0.60 (hexanes/EtOAc
1
= 2:1); IR (NaCl) 1709, 1486, 1166; H NMR (500 MHz, CDCl3) δ
7.38−7.19 (m, 5H), 6.50 (d, J = 15.8 Hz, 1H), 6.22−6.11 (m, 1H),
5.77 (d, J = 9.1 Hz, 1H), 4.85 (dd, J = 16.0, 7.2 Hz, 1H), 3.96−3.86
(m, 2H), 3.85−3.75 (m, 1H), 3.73−3.64 (m, 1H), 2.66 (t, J = 7.2 Hz,
2H), 2.11−1.84 (m, 4H), 1.42 (s, 9H); 13C NMR (125 MHz, CDCl3)
δ 199.6, 154.9, 137.0, 133.3, 128.4, 127.2, 126.0, 124.3, 79.6, 56.4, 53.8,
50.7, 40.0, 28.2, 26.0, 23.7; HRMS (ESI) calcd for C20H29N2O2S
(MH+) 361.1944, found 361.1945.
Allyl 1-(Cyclohex-2-enyl)-2-(pyrrolidin-1-yl)-2-thioxoethylcarba-
mate (25d). Compound 21 (151 mg, 0.66 mmol), FeBr3 (40 mg,
0.13 mmol), allylic bromide (153 μL, 1.33 mmol), and TEA (115 μL,
0.80 mmol) were reacted and worked up as described above. Product
25d: yellow oil, 58 mg, yield 29%; Rf = 0.60 (hexanes/EtOAc = 2: 1);
1
IR (NaCl) 2928, 1695, 1252; H NMR (600 MHz, CDCl3) δ 5.93
tert-Butyl ((S)-1-((2S,5S)-2,5-Diphenylpyrrolidin-1-yl)-1-thioxo-
(ddd, J = 22.5, 10.8, 5.6 Hz, 1H), 5.88−5.83 (m, 1H), 5.62 (dd, J = 8.0,
1.8 Hz, 1H), 5.38−5.19 (m, 3H), 4.61 (d, J = 5.5 Hz, 2H), 4.28−4.22
(m, 1H), 4.11 (d, J = 6.0 Hz, 2H), 2.12−1.94 (m, 4H), 1.81−1.73 (m,
pent-4-en-2-yl)carbamate (28a). Product 28a: yellow oil, Rf = 0.65
(hexanes/EtOAc = 3:1); IR (NaCl) 1711, 1493, 1437; [α]25.8 −46.3
D
(c 0.16, MeOH); 1H NMR (500 MHz, CDCl3) δ 7.40−7.08 (m, 10H),
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6.01 (d, J = 8.6 Hz, 1H), 5.77 (ddt, J = 17.3, 10.1, 7.3 Hz, 1H), 5.60
(dd, J = 36.9, 8.2 Hz, 2H), 5.18−5.08 (m, 2H), 4.66 (dd, J = 14.9, 6.9
Hz, 1H), 2.75−2.65 (m, 1H), 2.59−2.31 (m, 3H), 1.96 (dd, J = 12.5,
6.0 Hz, 1H), 1.80 (dd, J = 12.5, 6.1 Hz, 1H), 1.23 (s, 9H); 13C NMR
(125 MHz, CDCl3) δ 203.40, 153.34, 141.31, 141.03, 133.30, 128.90,
128.36, 127.68, 126.92, 125.77, 125.26, 118.54, 78.75, 68.33, 66.70,
56.76, 42.64, 33.20, 30.02, 28.25; HRMS (ESI) calcd for C26H33N2O2S
(MH+) 437.2257, found 437.2250. HPLC analysis: de >99%.
Chiralpak AD-RH column (CH3CN/H2O 60/40 to 70/30, in 30
min 0.5 mL/min, 254 nm); retention times of the only diastereomer
observed: 13.1 min (28a).
509.2462. HPLC analysis: de >97%. Chiralpak AD-RH column
(CH3CN/H2O 75/25 to 90/10 in 30 min, 0.5 mL/min, 254 nm);
retention times of the diastereomeric mixture observed: 5.6 min, 6.9
min(28e).
tert-Butyl ((S)-1-((S)-Cyclohex-2-en-1-yl)-2-((2S,5S)-2,5-diphenyl-
pyrrolidin-1-yl)-2-thioxoethyl)carbamate (28f). Compound 27 (51
mg, 0.13 mmol), n-butyllithium (1.6 M in hexanes, 0.18 mL, 0.28
mmol), and cinnamyl bromide (20 μL, 0.155 mmol) were reacted and
worked up as described above. Product 28f: yellow oil, 54 mg, yield
52%; Rf = 0.50 (hexanes/EtOAc = 3:1); [α]26.0 +70.1 (c 0.12,
D
MeOH); IR (NaCl) 1716, 1493, 1432; 1H NMR (500 MHz, CDCl3) δ
7.48−7.04 (m, 10H), 5.97 (d, J = 8.8 Hz, 1H), 5.91 (d, J = 9.5 Hz,
1H), 5.67 (d, J = 8.1 Hz, 1H), 5.49 (t, J = 9.9 Hz, 2H), 4.48 (t, J = 9.2
Hz, 1H), 2.82 (tt, J = 13.7, 7.0 Hz, 1H), 2.51−2.36 (m, 2H), 2.12−
1.91 (m, 3H), 1.77 (dd, J = 12.6, 6.2 Hz, 1H), 1.67−1.45 (m, 5H),
1.21 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 203.96, 153.57, 141.80,
141.64, 130.30, 128.99, 128.35, 127.70, 127.41, 127.06, 126.31, 125.15,
78.50, 68.89, 66.92, 59.61, 44.02, 33.43, 29.80, 28.26, 25.36, 24.17,
20.20; HRMS (ESI) calcd for C29H37N2O2S (MH+) 477.2570, found
477.2570. HPLC analysis: de >99%. Chiralpak AD-RH column
(CH3CN/H2O 60/40 to 70/30, in 30 min, 0.5 mL/min, 254 nm);
retention times of the only diastereomer observed: 21.9 min (28f).
General Procedure for the Oxidation−Iodolactonization−
Zinc Reduction To Generate Amino Acids 33−35. Compounds 3
(0.2 mmol) were dissolved in DCM (2 mL) and cooled to −78 °C. m-
CPBA (148 mg, 0.6 mmol) was added, and the suspension was stirred
and allowed to warm to ambient temperature in 1 h. The reaction was
diluted with ether and hexanes, washed with a saturated sodium
bicarbonate solution (5 mL × 3) and brine, and dried with anhydrous
MgSO4. The dry solvent was filtered and concentrated under reduced
pressure, and the residue was dissolved in 10 mL of THF/H2O
(1.5:1). To the solution was added iodine (152 mg, 0.6 mmol), and
the resultant mixture was stirred in the dark at ambient temperature
for 4 d. The reaction was quenched by the addition of 10% aqueous
Na2S2O3 (3 mL) and was extracted with DCM (5 mL × 3). The
combined organic layers were washed with 10% aqueous Na2S2O3 (3
mL × 2) and brine (3 mL) and dried over MgSO4. The dry solution
was concentrated under reduced pressure, and the crude product was
purified by flash column chromatography using a gradient solvent
mixture eluate (Hex/EtOAc = 8:1 to 4:1) to afford the iodolactone
compounds. The purified iodolactones were dissolved in glacial acetic
acid (10 mL) and treated with zinc dust (195 mg, 3 mmol). The
mixture was stirred for 2 h at 70 °C and then cooled to ambient
temperature. HCl (0.5 M, 10 mL) was added, the reaction mixture was
filtered and extracted with DCM (10 mL × 3), and the combined
organic layers were dried over MgSO4. The dry solution was
concentrated under reduced pressure, and the crude product was
purified by flash column chromatography to afford compounds 33−35
using a gradient solvent mixture eluate (hexanes/EtOAc = 2:1 to
hexanes/EtOAc/AcOH = 75:25:1).
tert-Butyl ((S)-1-((2S,5S)-2,5-Diphenylpyrrolidin-1-yl)-3,3-dimeth-
yl-1-thioxopent-4-en-2-yl)carbamate (28b). Product 28b: yellow oil,
Rf = 0.70 (hexanes/EtOAc = 3:1); IR (NaCl) 2975, 1720, 1489, 1422;
1
[α]26.0 −19.5 (c 0.12, MeOH); H NMR (600 MHz) δ 7.40−7.04
D
(m, 6H), 5.95−5.89 (m, 1H), 5.74 (d, J = 7.8 Hz, 1H), 5.63 (d, J = 9.1
Hz, 0H), 5.15−5.07 (m, 1H), 4.53 (d, J = 9.2 Hz, 0H), 2.80 (dq, J =
20.4, 6.9 Hz, 1H), 2.46−2.38 (m, 1H), 1.96 (dd, J = 12.6, 6.2 Hz, 1H),
1.75 (dd, J = 12.8, 6.4 Hz, 1H), 1.21 (s, 4H), 1.04 (s, 1H), 1.02 (s,
2H); 13C NMR (150 MHz, CDCl3) δ 202.4, 153.4, 145.1, 142.2,
141.7, 129.0, 128.2, 127.6, 127.0, 126.5, 125.1, 112.8, 78.5, 69.0, 62.2,
43.7, 33.6, 30.0, 28.2, 25.0, 23.1; HRMS (ESI) calcd for C28H37N2O2S
(MH+) 465.2570, found 465.2556. HPLC analysis: de >99%.
Chiralpak AD-RH column (CH3CN/H2O 60/40 to 80/20, in 40
min, 0.5 mL/min, 254 nm); retention times of the only diastereomer
observed: 15.0 min (12c).
tert-butyl (2S,3S)-1-((2S,5S)-2,5-diphenylpyrrolidin-1-yl)-3-meth-
yl-1-thioxopent-4-en-2-ylcarbamate (28c). Product 28c: yellow oil,
Rf = 0.65 (hexanes/EtOAc = 3:1); [α]24.2D −42.4 (c 0.24, MeOH); IR
1
(NaCl) 2975, 1716, 1426; H NMR (500 MHz, CDCl3) δ 7.42−7.11
(m, 10H), 6.00 (d, J = 8.8 Hz, 1H), 5.77−5.64 (m, 2H), 5.38 (d, J =
9.3 Hz, 1H), 4.94 (dd, J = 22.4, 13.7 Hz, 2H), 4.49−4.45 (m, 1H),
2.85−2.75 (m, 1H), 2.66−2.57 (m, 1H), 2.47 (ddd, J = 20.4, 11.5, 7.6
Hz, 1H), 1.99 (dd, J = 12.5, 6.0 Hz, 1H), 1.79 (dd, J = 12.6, 6.2 Hz,
1H), 1.19 (s, 9H), 1.04 (d, J = 6.8 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 203.3, 153.4, 141.6, 141.2, 139.2, 128.8, 128.4, 127.7, 127.0,
125.9, 125.3, 115.6, 78.5, 68.7, 66.8, 60.5, 46.4, 33.4, 29.8, 28.2, 17.2;
HRMS (ESI) calcd for C27H35N2O2S (MH+) 451.2414, found
451.2413. HPLC analysis: de = 94%. Chiralpak AD-RH column
(CH3CN/H2O 50/50 to 90/10 in 40 min, 0.5 mL/min, 254 nm);
retention times of the diastereomeric mixture observed: 22.5 min
(28c), 25.6 min.
tert-Butyl (2S,3R)-1-((2S,5S)-2,5-Diphenylpyrrolidin-1-yl)-3-phe-
nyl-1-thioxopent-4-en-2-ylcarbamate (28d). Product 28d: yellow
oil, Rf = 0.60 (hexanes/EtOAc = 2:1); [α]24.6D −75.1 (c 0.30, MeOH);
1
IR (NaCl) 2976, 1716, 1170; H NMR (500 MHz, CDCl3) δ 7.53−
7.02 (m, 15H), 6.23 (d, J = 7.1 Hz, 2H), 6.05−5.92 (m, 1H), 5.80 (dd,
J = 21.2, 8.0 Hz, 1H), 5.41−5.28 (m, 2H), 5.03−4.86 (m, 3H), 3.82
(dd, J = 27.1, 17.3 Hz, 1H), 2.42−2.11 (m, 2H), 1.71 (dd, J = 12.2, 5.5
Hz, 1H), 1.55 (dd, J = 12.3, 5.7 Hz, 1H), 1.21 (s, 9H); 13C NMR (125
MHz, CDCl3) δ 202.2, 153.1, 140.9, 140.6, 140.2, 138.4, 128.9, 128.6,
128.3, 127.6, 126.9, 126.2, 125.2, 125.2, 116.7, 78.6, 68.7, 67.1, 60.2,
59.8, 32.7, 30.0, 28.2; HRMS (ESI) calcd for C32H37N2O2S (MH+)
513.2570, found 513.2577. HPLC analysis: de = 82%. Chiralpak AD-
RH column (CH3CN/H2O 55/45, 0.5 mL/min, 254 nm); retention
times of the diastereomeric mixture observed: 29.7 min (28d), 33.9
min.
(S)-2-(Benzyloxycarbonylamino)-4-(ethoxycarbonyl)pent-4-enoic
Acid (33a). Compound 10a (112 mg, 0.27 mmol), m-CPBA (198 mg,
0.80 mmol), I2 (203 mg, 0.80 mmol), and Zn dust (261 mg, 4.03
mmol) were reacted and worked up as described above. Product 33a: a
colorless oil, 64 mg, yield 75%; Rf = 0.20 (hexanes/EtOAc/AcOH =
25:25:1); IR (NaCl) 1716.66, 1524.74, 1215.66; 1H NMR (500 MHz,
CDCl3) δ 10.26 (br, 1H), 7.41−7.27 (m, 5H), 6.27 (s, 1H), 5.69−5.63
(m, 2H), 5.09 (q, J = 12.3 Hz, 2H), 4.56 (dd, J = 13.0, 7.9 Hz, qH),
4.20 (q, J = 7.0 Hz, 2H), 2.92 (dd, J = 14.1, 4.8 Hz, 1H), 2.72 (dd, J =
14.1, 8.3 Hz, 1H), 1.28 (t, J = 7.1 Hz, 3H); 13C (150 MHz, CDCl3) δ
175.69, 166.91, 156.07, 136.19, 135.57, 129.02, 128.45, 128.13, 128.01,
67.09, 61.22, 53.53, 34.42, 14.03; HRMS (ESI) calcd for
C16H19NNaO6 (MNa+) 344.1105, found 344.1106. HPLC analysis:
de = 69%. Chiralpak AD-RH column (CH3CN/H2O 27.5/72.5, 0.5
mL/min, 254 nm); retention times the racemic mixture observed: 23.8
min, 26.3 min; retention time of the enantiorich product observed:
23.2 min (33a), 25.5 min.
(S)-Ethyl 2-((S)-1-((tert-Butoxycarbonyl)amino)-2-((2S,5S)-2,5-di-
phenylpyrrolidin-1-yl)-2-thioxoethyl)but-3-enoate (28e). Product
28e: clear oil, Rf = 0.60 (hexanes/EtOAc = 3:1); [α]26.0 −79.8 (c
D
0.06, MeOH); IR (NaCl) 1723, 1447; 1H NMR (500 MHz, CDCl3) δ
7.48−7.01 (m, 10H), 6.27 (d, J = 8.0 Hz, 1H), 5.91 (d, J = 8.6 Hz,
1H), 5.71 (dt, J = 16.9, 9.7 Hz, 1H), 5.31−4.97 (m, 4H), 4.33−4.19
(m, 1H), 4.16−4.06 (m, 1H), 3.69 (t, J = 9.4 Hz, 1H), 2.76 (ddd, J =
20.3, 10.9, 6.9 Hz, 1H), 2.53−2.44 (m, 1H), 1.90 (dd, J = 12.4, 5.9 Hz,
1H), 1.75 (dd, J = 12.5, 6.0 Hz, 1H), 1.23 (t, J = 7.1 Hz, 3H), 1.16 (s,
9H); 13C NMR (125 MHz, CDCl3) δ 200.87, 172.41, 152.89, 141.59,
141.45, 132.45, 128.62, 128.26, 127.59, 126.77, 125.61, 125.53, 120.50,
78.85, 68.93, 67.08, 60.96, 59.77, 56.44, 33.01, 30.20, 28.18, 14.05;
HRMS (ESI) calcd for C29H37N2O4S (MH+) 509.2469, found
(2S,3S)-2-(Benzyloxycarbonylamino)-3-(methoxycarbonyl)pent-
4-enoic Acid (33c). Compound 10c (78.8 mg, 0.20 mmol), m-CPBA
(144 mg, 0.58 mmol), I2 (148 mg, 0.58 mmol), and Zn dust (190 mg,
1298
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Article
2.93 mmol) were reacted and worked up as described above. Product
66.21, 61.61, 52.16, 29.70, 14.01; HRMS (ICR) calcd for C12H16NO6
(M − H−) 270.0983, found 270.0983.
33c: a colorless oil, 47 mg, yield 79%; Rf = 0.30 (hexanes/EtOAc/
AcOH = 25:25:1); [α]23.0 −31.4 (c 0.59, MeOH); IR (NaCl)
(S)-2-(((Allyloxy)carbonyl)amino)-2-((S)-cyclohex-2-en-1-yl)acetic
Acid (35d). Compound 25d (49 mg, 0.17 mmol), m-CPBA (128 mg,
0.48 mmol), I2 (123 mg, 0.48 mmol), and Zn dust (156 mg, 2.40
mmol) were reacted and worked up as described above. Product 35d:
a colorless oil, 28 mg, yield 68%; Rf = 0.65 (hexanes/EtOAc/AcOH =
25:25:1); IR (NaCl) 2927, 1720; 1H NMR (500 MHz, CDCl3) δ 9.10
(br, 1H), 5.90 (ddd, J = 22.3, 10.7, 5.5 Hz, 1H), 5.85−5.80 (m, 1H),
5.54 (d, J = 9.8 Hz, 1H), 5.40−5.25 (m, 2H), 4.56 (d, J = 4.9 Hz, 2H),
4.47−4.39 (m, 1H), 2.85−2.65 (m, 1H), 2.05−1.90 (m, 2H), 1.85−
1.75 (m, 1H), 1.75−1.62 (m, 1H), 1.58−1.46 (m, 1H), 1.34 (dd, J =
23.0, 11.1 Hz, 1H);13C NMR (126 MHz, CDCl3) δ 176.38, 156.27,
132.47, 130.51, 126.65, 117.94, 66.02, 57.30, 38.34, 29.68, 24.70,
23.85, 21.36; HRMS (ICR) calcd for C12H16NO4 (M − H−) 238.1085,
found 238.1087.
D
1732.69, 1524.79, 1258.23; 1H NMR (500 MHz, CDCl3) δ 10.43 (br,
1H), 7.38−7.27 (m, 5H), 5.97−5.86 (m, 1H), 5.58 (d, J = 8.6 Hz,
1H), 5.31−5.23 (m, 2H), 5.10 (s, 2H), 4.81 (dd, J = 8.3, 5.4 Hz, 1H),
3.69 (s, 3H), 3.61 (dd, J = 8.4, 5.4 Hz, 1H); 13C (125 MHz, CDCl3) δ
174.32, 171.36, 155.93, 135.84, 130.76, 128.46, 128.20, 128.04, 121.02,
67.37, 55.66, 52.53, 52.12; HRMS (ESI) calcd for C15H17NNaO6
(MNa+) 330.0948, found 330.0941. HPLC analysis: de = 99%.
Chiralpak AD-RH column (CH3CN/H2O 27.5/72.5, 0.5 mL/min, 254
nm); retention times the racemic mixture observed: 15.5 min, 19.5
min; retention time of the enantiopure product observed: 15.7 min
(33c).
(2S,3S)-2-(Benzyloxycarbonylamino)-3-(ethoxycarbonyl)pent-4-
enoic Acid (33d). Compound 10d (86 mg, 0.21 mmol), m-CPBA (152
mg, 0.62 mmol), I2 (156 mg, 0.62 mmol), and Zn dust (205 mg, 3.15
mmol) were reacted and worked up as described above. Product 33d:
a colorless oil, 50 mg, yield 76%; Rf = 0.20 (hexanes/EtOAc/AcOH =
(2S,3S)-2-(((Allyloxy)carbonyl)amino)-3-((2-oxo-2-phenylethoxy)-
carbonyl)pent-4-enoic Acid (35e). Compound 25e (70 mg, 0.16
mmol), m-CPBA (120 mg, 0.48 mmol), I2 (120 mg, 0.48 mmol), and
Zn dust (156 mg, 2.40 mmol) were reacted and worked up as
described above. Product 35e: a colorless oil, 18 mg, yield 30%; Rf =
0.65 (hexanes/EtOAc/AcOH = 25:25:1); IR (NaCl) 2924, 2853,
1700; 1H NMR (500 MHz, CDCl3) δ 7.92 (d, J = 7.6 Hz, 2H), 7.63 (t,
J = 7.2 Hz, 1H), 7.50 (t, J = 7.7 Hz, 2H), 6.06 (dt, J = 19.0, 9.6 Hz,
1H), 5.94 (ddd, J = 22.6, 10.8, 5.7 Hz, 1H), 5.84 (d, J = 8.7 Hz, 1H),
5.37 (dd, J = 29.6, 18.2 Hz, 4H), 5.24 (d, J = 10.6 Hz, 1H), 4.86 (s,
1H), 4.62 (d, J = 5.3 Hz, 2H), 3.83 (s, 2H); 13C NMR (125 MHz,
CDCl3) δ 192.07, 176.18, 134.10, 133.94, 132.47, 130.92, 128.91,
127.89, 121.25, 117.92, 100.00, 66.71, 66.18, 29.74, 20.60; HRMS
(ESI) calcd for C18H19NNaO7 (MNa+) 384.1054, found 384.1047.
25:25:1), [α]24.8 −28.8 (c 0.38, MeOH); IR (NaCl) 1732.57,
D
1
1246.43, 1195.13; H NMR (600 MHz, CDCl3) δ 10.20 (br, 1H),
7.40−7.27 (m, 5H), 5.97−5.89 (m, 1H), 5.53 (d, J = 8.6 Hz, 1H),
5.28−5.23 (m, 2H), 5.11 (s, 2H), 4.82 (dd, J = 8.1, 5.5 Hz, 1H), 4.16
(dd, J = 13.9, 6.9 Hz, 2H), 3.59 (dd, J = 8.4, 5.4 Hz, 1H), 1.24 (t, J =
7.0 Hz, 3H); 13C (150 MHz, CDCl3) δ 174.61, 170.88, 155.95, 135.89,
130.90, 128.50, 128.24, 128.09, 120.97, 67.34, 61.59, 55.63, 52.18,
13.95; HRMS (ESI) calcd for C16H20NO6 (MH+) 322.1285, found
322.1284. HPLC analysis: de = 99%. Chiralpak AD-RH column
(CH3CN/H2O 27.5:72.5, 0.5 mL/min, 254 nm); retention times the
racemic mixture observed: 22.7 min, 28.1 min; retention time of the
enantiopure product observed: 21.5 min (33d).
ASSOCIATED CONTENT
■
(2S,3S)-2-((tert-Butoxycarbonyl)amino)-3-methylpent-4-enoic
Acid (34b). Compound 32c (45 mg, 0.10 mmol), m-CPBA (75 mg,
0.30 mmol), I2 (76 mg, 0.30 mmol), and Zn dust (98 mg, 1.50 mmol)
were reacted and worked up as described above. Product 34b: a
colorless oil, 16 mg, yield 70%; Rf = 0.70 (hexanes/EtOAc/AcOH =
S
* Supporting Information
Spectroscopic characterization (1H NMR, 13C NMR) of all new
compounds and X-ray crystallography data. This material is
available free of charge via the Internet at http://pubs.acs.org.
25:25:1); [α]25.6 +26.4 (c 0.06, MeOH); IR (NaCl) 2924, 1717,
D
1164; 1H NMR (500 MHz, CDCl3) δ 5.77−5.70 (m, 1H), 5.20−5.11
(m, 2H), 4.95 (d, J = 8.6 Hz, 1H), 4.34 (dd, J = 8.5, 4.6 Hz, 1H), 2.85
(d, J = 5.6 Hz, 1H), 1.47 (s, 9H), 1.15 (d, J = 6.9 Hz, 3H). 13C NMR
(125 MHz, CDCl3) δ 176.80, 155.89, 137.38, 117.18, 80.23, 57.63,
39.62, 28.27, 16.07; HRMS (ICR) calcd for C11H18NO4 (M − H−)
228.1241, found 228.1244. HPLC analysis: de = 96%. Chiralpak AD-
RH column (CH3CN/H2O 27.5/72.5, 0.5 mL/min, 254 nm);
retention times the racemic mixture observed: 20.1 min, 22.2 min;
retention time of the enantiorich product observed: 21.7 min, 23.2
(33d).
(2S,3S)-2-((tert-Butoxycarbonyl)amino)-3-(ethoxycarbonyl)pent-
4-enoic Acid (34c). Compound 23c (84 mg, 0.24 mmol), m-CPBA
(174 mg, 0.71 mmol), I2 (180 mg, 0.71 mmol), and Zn dust (234 mg,
3.60 mmol) were reacted and worked up as described above. Product
34c: a colorless oil, 57 mg, yield 68%; Rf = 0.75 (hexanes/EtOAc/
AcOH = 25:25:1); IR (NaCl) 2924, 1717, 1161; 1H NMR (500 MHz,
CDCl3) δ 5.23 (d, J = 7.4 Hz, 1H), 4.91 (t, J = 8.4 Hz, 1H), 4.83 (dd, J
= 4.9, 2.4 Hz, 2H), 4.32−4.18 (m, 2H), 3.62 (dd, J = 9.1, 1.8 Hz, 1H),
3.43 (ddd, J = 18.3, 10.8, 6.2 Hz, 2H), 1.47 (s, 9H), 1.32 (t, J = 7.2 Hz,
3H). 13C NMR (125 MHz, CDCl3) δ 172.10, 169.24, 155.18, 81.14,
78.35, 62.03, 50.77, 48.87, 28.21, 14.15, 4.75; HRMS (ICR) calcd for
C13H20NO6 (M − H−) 286.1296, found 286.1297.
AUTHOR INFORMATION
Corresponding Author
*Tel: (520) 621- 6332. Fax: (520) 621-8407. E-mail: hruby@
email.arizona.edu.
■
ACKNOWLEDGMENTS
■
This work was supported by US Public Health Service Grant
No. DK 17420 and the National Institute of Drug Abuse
(Grant Nos. DA 06284, DA 13449). We also thank Prof.
Richard Glass (the University of Arizona) for useful
discussions.
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